title: Vascularized and functional human liver from an iPSC-derived organ bud transplant.
abstract: A critical shortage of donor organs for treating end-stage organ failure highlights the urgent need for generating organs from human induced pluripotent stem cells (iPSCs). Despite many reports describing functional cell differentiation, no studies have succeeded in generating a three-dimensional vascularized organ such as liver. Here we show the generation of vascularized and functional human liver from human iPSCs by transplantation of liver buds created in vitro (iPSC-LBs). Specified hepatic cells (immature endodermal cells destined to track the hepatic cell fate) self-organized into three-dimensional iPSC-LBs by recapitulating organogenetic interactions between endothelial and mesenchymal cells. Immunostaining and gene-expression analyses revealed a resemblance between in vitro grown iPSC-LBs and in vivo liver buds. Human vasculatures in iPSC-LB transplants became functional by connecting to the host vessels within 48 hours. The formation of functional vasculatures stimulated the maturation of iPSC-LBs into tissue resembling the adult liver. Highly metabolic iPSC-derived tissue performed liver-specific functions such as protein production and human-specific drug metabolism without recipient liver replacement. Furthermore, mesenteric transplantation of iPSC-LBs rescued the drug-induced lethal liver failure model. To our knowledge, this is the first report demonstrating the generation of a functional human organ from pluripotent stem cells. Although efforts must ensue to translate these techniques to treatments for patients, this proof-of-concept demonstration of organ-bud transplantation provides a promising new approach to study regenerative medicine.
authors.affiliation: Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa 236-0004, Japan. (ttakebe@yokohama-cu.ac.jp
authors.forename: Takanori
authors.initials: T
authors.lastname: Takebe
authors.forename: Keisuke
authors.initials: K
authors.lastname: Sekine
authors.forename: Masahiro
authors.initials: M
authors.lastname: Enomura
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Koike
authors.forename: Masaki
authors.initials: M
authors.lastname: Kimura
authors.forename: Takunori
authors.initials: T
authors.lastname: Ogaeri
authors.forename: Ran-Ran
authors.initials: RR
authors.lastname: Zhang
authors.forename: Yasuharu
authors.initials: Y
authors.lastname: Ueno
authors.forename: Yun-Wen
authors.initials: YW
authors.lastname: Zheng
authors.forename: Naoto
authors.initials: N
authors.lastname: Koike
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Aoyama
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Adachi
authors.forename: Hideki
authors.initials: H
authors.lastname: Taniguchi
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage; D056486:Chemical and Drug Induced Liver Injury / Q000628:therapy; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism / Q000637:transplantation; D020869:Gene Expression Profiling; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism / Q000637:transplantation; D008099:Liver / Q000098:blood supply* / Q000196:embryology / Q000378:metabolism / Q000502:physiology*; D017093:Liver Failure / Q000628:therapy; D016031:Liver Transplantation; D008648:Mesoderm / Q000166:cytology / Q000378:metabolism / Q000637:transplantation; D051379:Mice; D044968:Regenerative Medicine / Q000379:methods*; D046509:Tissue Culture Techniques